JP5808319B2 - Treatment of cognitive impairment using specific α7 nicotinic acid receptors in combination with acetylcholinesterase inhibitors - Google Patents
Treatment of cognitive impairment using specific α7 nicotinic acid receptors in combination with acetylcholinesterase inhibitors Download PDFInfo
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Description
ニコチン性アセチルコリン受容体（ｎＡＣｈＲ）は、アセチルコリンによって活性化されるイオンチャンネルのファミリーを形成する。機能的受容体は５つのサブユニットを含有し、数多くの受容体サブタイプがある。研究により中枢性ニコチン性アセチルコリン受容体が学習及び記憶に関与することが示されている。α７サブタイプのニコチン性アセチルコリン受容体は海馬及び大脳皮質に分布している。 Nicotinic acetylcholine receptors (nAChRs) form a family of ion channels that are activated by acetylcholine. Functional receptors contain five subunits and there are numerous receptor subtypes. Studies have shown that central nicotinic acetylcholine receptors are involved in learning and memory. The α7 subtype nicotinic acetylcholine receptor is distributed in the hippocampus and cerebral cortex.
WO 03/055878には、α７ ｎＡＣｈＲの種々のアゴニストが認知機能の改善に有用と言われていることが記載されている。WO 03/055878は、α７ ｎＡＣｈＲの特定のアゴニストが知覚（perception）、集中（concentration）、学習又は記憶の改善、特に、例えば、軽度認知機能障害、加齢に伴う学習及び記憶の障害、加齢に伴う記憶喪失、アルツハイマー病（ＡＤ）、統合失調症及び特定の他の認知障害のような状態／疾患／症候群において生じるもののような認知機能障害後の知覚、集中、学習又は記憶の改善に有用であることを示唆している。これらの化合物の中で、（Ｒ）−７−クロロ−Ｎ−（キヌクリジン−３−イル）ベンゾ［ｂ］チオフェン−２−カルボキサミドが記載される。 WO 03/055878 describes that various agonists of α7 nAChR are said to be useful for improving cognitive function. WO 03/055878 states that certain agonists of α7 nAChR improve perception, concentration, learning or memory, in particular, for example, mild cognitive impairment, learning and memory impairment associated with aging, aging Useful for improving perception, concentration, learning or memory after cognitive impairment, such as that occurring in conditions / diseases / syndromes such as memory loss, Alzheimer's disease (AD), schizophrenia and certain other cognitive impairments It is suggested that. Among these compounds, (R) -7-chloro-N- (quinuclidin-3-yl) benzo [b] thiophene-2-carboxamide is described.
一部の人は、アルツハイマー病患者において観察される認知低下及び機能低下が中枢神経系におけるコリン作動性欠損に起因すると考えている。ＡＤを治療するために使用されている少なくとも４つの薬物（タクリン、ドネペジル（塩酸ドネペジル；１−ベンジル−４−［（５，６−ジメトキシ−１−インダノン）−２−イル］メチルピペリジン一塩酸塩）、リバスチグミン（（Ｓ）−Ｎ−エチル−Ｎ−メチル−３−［１−（ジメチルアミノ）エチル］−フェニルカルバメート）及びガランタミン（臭化水素酸ガランタミン;（４ａＳ，６Ｒ，８ａＳ）−４ａ，５，９，１０，１１，１２−ヘキサヒドロ−３−メトキシ−１１−メチル−６Ｈ−ベンゾフロ［３ａ，３，２−ｅｆ］［２］ベンズアゼピン−６−オール臭化水素酸塩））は、ＣＮＳにおいてアセチルコリンを増加させるアセチルコリンエステラーゼ阻害剤として働くように見える。 Some believe that the cognitive and functional decline observed in Alzheimer's patients is due to cholinergic deficits in the central nervous system. At least four drugs used to treat AD (tacrine, donepezil (donepezil hydrochloride; 1-benzyl-4-[(5,6-dimethoxy-1-indanone) -2-yl] methylpiperidine monohydrochloride) ), Rivastigmine ((S) -N-ethyl-N-methyl-3- [1- (dimethylamino) ethyl] -phenylcarbamate) and galantamine (galantamine hydrobromide; (4aS, 6R, 8aS) -4a, 5,9,10,11,12-hexahydro-3-methoxy-11-methyl-6H-benzofuro [3a, 3,2-ef] [2] benzazepine-6-ol hydrobromide)) Appears to act as an acetylcholinesterase inhibitor that increases acetylcholine in
驚いたことに、（Ｒ）−７−クロロ−Ｎ−（キヌクリジン−３−イル）ベンゾ［ｂ］チオフェン−２−カルボキサミドが、アセチルコリンエステラーゼ阻害剤（例えば、ドネペジル又はリバスチグミン）を用いて治療されているアルツハイマー病患者において認知機能を改善しうることが見出されている。この方法は、アセチルコリンエステラーゼ阻害剤の投与から生じる認知機能の１以上の側面における増進から既に利益を得ている患者の認知機能を改善しうる。従って、認知機能の１以上の側面においてアセチルコリンエステラーゼ阻害剤から既に利益を得ている患者が、（Ｒ）−７−クロロ−Ｎ−（キヌクリジン−３−イル）ベンゾ［ｂ］チオフェン−２−カルボキサミド及びその製薬上許容しうる塩の投与から、認知機能の１以上の側面において、さらに利益を得ることができる。 Surprisingly, (R) -7-chloro-N- (quinuclidin-3-yl) benzo [b] thiophene-2-carboxamide was treated with acetylcholinesterase inhibitors (eg donepezil or rivastigmine). It has been found that cognitive function can be improved in patients with Alzheimer's disease. This method may improve the cognitive function of patients already benefiting from enhancements in one or more aspects of cognitive function resulting from administration of an acetylcholinesterase inhibitor. Thus, a patient who has already benefited from an acetylcholinesterase inhibitor in one or more aspects of cognitive function is (R) -7-chloro-N- (quinuclidin-3-yl) benzo [b] thiophene-2-carboxamide. And the administration of pharmaceutically acceptable salts thereof can further benefit in one or more aspects of cognitive function.
驚いたことに、（Ｒ）−７−クロロ−Ｎ−（キヌクリジン−３−イル）ベンゾ［ｂ］チオフェン−２−カルボキサミドが無症候性投与量（即ち、記憶を改善しない投与量）でアセチルコリンエステラーゼ阻害剤（これも無症候性投与量で投与される）と組み合わせて投与される場合、記憶が改善されうることも見出されている。従って、患者は、非常に少なく、副作用を低減するか又は副作用を回避する投与量でそれぞれが投与される薬物の組み合わせから、利益（例えば、記憶の改善又は認知機能の改善）を体験することができる。更に、薬物の組み合わせは、より広い範囲の患者のために及び／又はより長い治療期間にわたり、利益を提供しうる。例えば、特定のアセチルコリンエステラーゼ阻害剤は、数ヶ月間の治療の後に有効性の減少を示しうるのに対し、この組み合わせはより長期間の有効性を提供しうる。 Surprisingly, (R) -7-chloro-N- (quinuclidin-3-yl) benzo [b] thiophene-2-carboxamide is an asymptomatic dose (ie, a dose that does not improve memory) at acetylcholinesterase. It has also been found that memory can be improved when administered in combination with an inhibitor (also administered at an asymptomatic dose). Thus, patients may experience benefits (eg, improved memory or improved cognitive function) from a combination of drugs that are each administered in doses that are very low and reduce or avoid side effects. it can. Furthermore, drug combinations may provide benefits for a wider range of patients and / or over longer treatment periods. For example, certain acetylcholinesterase inhibitors may show reduced efficacy after several months of treatment, whereas this combination may provide longer term efficacy.
患者は、以下の１以上において利益を得ることができる：処理速度、注意力／ビジランス、作業記憶、視覚学習、言語学習、視覚学習、推論／問題解決、実行機能、及び社会的認知。重要なことに、（Ｒ）−７−クロロ−Ｎ−（キヌクリジン−３−イル）ベンゾ［ｂ］チオフェン−２−カルボキサミド及びその製薬上許容しうる塩は、認知機能を改善するために、そのような既に治療された患者において少ない投与量で、例えば以下の１日経口投与量（又はそれ以下）で使用されうる：３ｍｇ、２．７０ｍｇ、２．５０ｍｇ、２．２５ｍｇ、２ｍｇ、１．７５ｍｇ、１．５０ｍｇ、１．２５ｍｇ、１ｍｇ、０．７、０．５、０．３ｍｇ又はわずか０．１ｍｇ。従って、例えば、それは０．０５〜１．５ｍｇの１日投与量で、好ましくは１ｍｇ／日又は０．３ｍｇ／日で投与されうる。無症候性投与量を投与する場合において、認知機能の改善のための他の薬剤の非存在下で投与される場合、（Ｒ）−７−クロロ−Ｎ−（キヌクリジン−３−イル）ベンゾ［ｂ］チオフェン−２−カルボキサミド及びその製薬上許容しうる塩は、０．５ｍｇ未満、０．３ｍｇ未満、０．１ｍｇ未満、０．０５ｍｇ未満、０．０３ｍｇ未満又は０．０１ｍｇ未満の１日経口投与量で使用されうる。無症候性レベルでの使用のために、認知機能を改善するための他の薬剤の非存在下で投与される場合、（Ｒ）−７−クロロ−Ｎ−（キヌクリジン−３−イル）ベンゾ［ｂ］チオフェン−２−カルボキサミド及びその製薬上許容しうる塩は、０．５ｎＭ未満、０．４ｎＭ未満、０．３ｎＭ未満、０．２ｎＭ未満又は０．１ｎＭ未満で使用されうる。 Patients can benefit from one or more of the following: processing speed, attention / vigilance, working memory, visual learning, language learning, visual learning, reasoning / problem solving, executive function, and social cognition. Importantly, (R) -7-chloro-N- (quinuclidin-3-yl) benzo [b] thiophene-2-carboxamide and its pharmaceutically acceptable salts are used to improve cognitive function. May be used in small doses, such as the following daily oral doses (or less) in already treated patients such as: 3 mg, 2.70 mg, 2.50 mg, 2.25 mg, 2 mg, 1.75 mg 1.50 mg, 1.25 mg, 1 mg, 0.7, 0.5, 0.3 mg or only 0.1 mg. Thus, for example, it may be administered at a daily dosage of 0.05 to 1.5 mg, preferably 1 mg / day or 0.3 mg / day. When administering asymptomatic doses, when administered in the absence of other drugs for improving cognitive function, (R) -7-chloro-N- (quinuclidin-3-yl) benzo [ b] Thiophene-2-carboxamide and its pharmaceutically acceptable salts are daily doses of less than 0.5 mg, less than 0.3 mg, less than 0.1 mg, less than 0.05 mg, less than 0.03 mg or less than 0.01 mg. Can be used in dosages. When used in the absence of other drugs to improve cognitive function for use at asymptomatic levels, (R) -7-chloro-N- (quinuclidin-3-yl) benzo [ b] Thiophene-2-carboxamide and its pharmaceutically acceptable salts may be used at less than 0.5 nM, less than 0.4 nM, less than 0.3 nM, less than 0.2 nM or less than 0.1 nM.
ドネペジル（donepizil）について、（Ｒ）−７−クロロ−Ｎ−（キヌクリジン−３−イル）ベンゾ［ｂ］チオフェン−２−カルボキサミド又はその製薬上許容しうる塩と共に使用される１日投与量は、１０ｍｇ、５ｍｇ、４．５ｍｇ、４ｍｇ、３．５ｍｇ、３ｍｇ、２．５ｍｇ、２ｍｇ、１ｍｇ又は０．５ｍｇでありうる。１日投与量は、５から０．５ｍｇの間（例えば、４．５〜１．０ｍｇ／日、４．５〜２．０ｍｇ／日、４．０〜２．０又は２．５ｍｇ／日）でありうる。リバスチグミン（rivistigmine）について、併用のための１日投与量は、１１、１０、９、８、７、６又は５ｍｇでありうる。ガランタミンについて、併用のための１日投与量は、２０、１５、１３、１２、１１、１０、９、８、７、６又は５ｍｇでありうる。アセチルコリンエステラーゼ阻害剤について、記憶又は認知機能の改善における有効性のために、それらは少なくとも６５％の赤血球アセチルコリンエステラーゼ阻害を達成するように投与されなければならないことが理解される。本明細書中に記載される方法において、アセチルコリンエステラーゼ阻害剤は、わずか５５％（５０、４５、４０、３５又は３０％阻害）を達成する、より少ない投与量で投与されうる。 For donepezil, the daily dose used with (R) -7-chloro-N- (quinuclidin-3-yl) benzo [b] thiophene-2-carboxamide or a pharmaceutically acceptable salt thereof is: It can be 10 mg, 5 mg, 4.5 mg, 4 mg, 3.5 mg, 3 mg, 2.5 mg, 2 mg, 1 mg or 0.5 mg. Daily dose is between 5 and 0.5 mg (eg, 4.5-1.0 mg / day, 4.5-2.0 mg / day, 4.0-2.0 or 2.5 mg / day) It can be. For rivistigmine, the daily dose for combination may be 11, 10, 9, 8, 7, 6 or 5 mg. For galantamine, the daily dosage for combination may be 20, 15, 13, 12, 11, 10, 9, 8, 7, 6 or 5 mg. It is understood that for acetylcholinesterase inhibitors, for efficacy in improving memory or cognitive function, they must be administered to achieve at least 65% erythrocyte acetylcholinesterase inhibition. In the methods described herein, the acetylcholinesterase inhibitor may be administered at a lower dosage that achieves only 55% (50, 45, 40, 35 or 30% inhibition).
本明細書中に、（Ｒ）−７−クロロ−Ｎ−（キヌクリジン−３−イル）ベンゾ［ｂ］チオフェン−２−カルボキサミド又はその製薬上許容しうる塩、及びアセチルコリンエステラーゼ阻害剤を患者に投与することを含む、認知機能を改善する方法が記載される。種々の場合において：患者はアルツハイマー病又はプレアルツハイマー病と診断されており、患者は軽度から中等度のアルツハイマー病と診断されており、患者は中等度から重度のアルツハイマー病と診断されており、アセチルコリンエステラーゼ阻害剤はタクリン、ドネペジル、リバスチグミン及びガランタミンから選択され、アセチルコリンエステラーゼ阻害剤はドネペジル、リバスチグミン及びガランタミンから選択され、アセチルコリンエステラーゼ阻害剤はドネペジル及びリバスチグミンから選択され、患者は（Ｒ）−７−クロロ−Ｎ−（キヌクリジン−３−イル）ベンゾ［ｂ］チオフェン−２−カルボキサミド又はその製薬上許容しうる塩を投与されるより先に一定期間アセチルコリンエステラーゼ阻害剤を投与されており、先の投与は少なくとも１ヶ月間であり、先の投与は少なくとも３ヶ月間であり、そして先の投与は少なくとも６ヶ月間である。特定の場合において：該方法は以下の１以上を改善する：学習、遅延記憶（delayed memory）、注意力、作業記憶、視覚学習、処理速度、ビジランス、言語学習、視覚運動（visual motor）機能、社会的認知、長期記憶又は実行機能。 In this specification, (R) -7-chloro-N- (quinuclidin-3-yl) benzo [b] thiophene-2-carboxamide or a pharmaceutically acceptable salt thereof, and an acetylcholinesterase inhibitor are administered to a patient. A method for improving cognitive function is described. In various cases: the patient has been diagnosed with Alzheimer's disease or pre-Alzheimer's disease, the patient has been diagnosed with mild to moderate Alzheimer's disease, the patient has been diagnosed with moderate to severe Alzheimer's disease, and acetyl The cholinesterase inhibitor is selected from tacrine, donepezil, rivastigmine and galantamine, the acetylcholinesterase inhibitor is selected from donepezil, rivastigmine and galantamine, the acetylcholinesterase inhibitor is selected from donepezil and rivastigmine, and the patient is (R) -7-chloro -N- (quinuclidin-3-yl) benzo [b] thiophene-2-carboxamide or a pharmaceutically acceptable salt thereof is administered for a certain period of time before an acetylcholinesterase inhibitor is administered; Administration is at least one month, administered earlier is at least 3 months, and administration ahead of at least 6 months. In certain cases: the method improves one or more of the following: learning, delayed memory, attention, working memory, visual learning, processing speed, vigilance, language learning, visual motor function, Social cognition, long-term memory or executive function.
（Ｒ）−７−クロロ−Ｎ−（キヌクリジン−３−イル）ベンゾ［ｂ］チオフェン−２−カルボキサミド又はその製薬上許容しうる塩を無症候性投与量（アセチルコリンエステラーゼ（acetylcholinestesterase）阻害剤の非存在下で投与された場合、記憶を改善しない投与量）で、そしてアセチルコリンエステラーゼ阻害剤も無症候性投与量（（Ｒ）−７−クロロ−Ｎ−（キヌクリジン−３−イル）ベンゾ［ｂ］チオフェン−２−カルボキサミド又はその製薬上許容しうる塩の非存在下で投与された場合、記憶を改善しない投与量）で、患者に投与することを含む、認知機能を改善する方法も記載される。種々の場合において：（Ｒ）−７−クロロ−Ｎ−（キヌクリジン−３−イル）ベンゾ［ｂ］チオフェン−２−カルボキサミド又はその製薬上許容しうる塩は、１．０ｍｇ／日；０．５ｍｇ／日；０．３ｍｇ／日；又は０．１ｍｇ／日で経口投与される。種々の場合において：アセチルコリンエステラーゼ阻害剤はドネペジルであり、且つ５ｍｇ／日；４．５ｍｇ／日；４．０ｍｇ／日；２．５ｍｇ／日；１．５ｍｇ／日又はそれ以下；１．０ｍｇ／日で経口投与され；そしてアセチルコリンエステラーゼ阻害剤は、定常状態で１０〜６５％の赤血球アセチルコリンエステラーゼ阻害を達成する投与量で投与される。 (R) -7-Chloro-N- (quinuclidin-3-yl) benzo [b] thiophene-2-carboxamide or a pharmaceutically acceptable salt thereof asymptomatic dose (non-acetylcholinestesterase inhibitor) Doses that do not improve memory when administered in the presence) and acetylcholinesterase inhibitors are also asymptomatic doses ((R) -7-chloro-N- (quinuclidin-3-yl) benzo [b] Also described is a method for improving cognitive function comprising administering to a patient at a dose that does not improve memory when administered in the absence of thiophene-2-carboxamide or a pharmaceutically acceptable salt thereof. . In various cases: (R) -7-chloro-N- (quinuclidin-3-yl) benzo [b] thiophene-2-carboxamide or a pharmaceutically acceptable salt thereof is 1.0 mg / day; 0.5 mg / Day; 0.3 mg / day; or 0.1 mg / day. In various cases: the acetylcholinesterase inhibitor is donepezil and 5 mg / day; 4.5 mg / day; 4.0 mg / day; 2.5 mg / day; 1.5 mg / day or less; 1.0 mg / day The acetylcholinesterase inhibitor is administered at a dose that achieves 10-65% erythrocyte acetylcholinesterase inhibition at steady state.
（Ｒ）−７−クロロ−Ｎ−（キヌクリジン−３−イル）ベンゾ［ｂ］チオフェン−２−カルボキサミド又はその製薬上許容しうる塩、及びアセチルコリンエステラーゼ阻害剤を含有する医薬組成物も記載される。種々の場合において：アセチルコリンエステラーゼ阻害剤はタクリン、ドネペジル、リバスチグミン及びガランタミンから選択される；アセチルコリンエステラーゼ阻害剤はドネペジル、リバスチグミン及びガランタミンから選択される；アセチルコリンエステラーゼ阻害剤はドネペジル及びリバスチグミンから選択される；そしてアセチルコリンエステラーゼ阻害剤はドネペジルである。 Also described is a pharmaceutical composition comprising (R) -7-chloro-N- (quinuclidin-3-yl) benzo [b] thiophene-2-carboxamide or a pharmaceutically acceptable salt thereof, and an acetylcholinesterase inhibitor. . In various cases: the acetylcholinesterase inhibitor is selected from tacrine, donepezil, rivastigmine and galantamine; the acetylcholinesterase inhibitor is selected from donepezil, rivastigmine and galantamine; the acetylcholinesterase inhibitor is selected from donepezil and rivastigmine; And the acetylcholinesterase inhibitor is donepezil.
１．０ｍｇ以下の（Ｒ）−７−クロロ−Ｎ−（キヌクリジン−３−イル）ベンゾ［ｂ］チオフェン−２−カルボキサミド又はその製薬上許容しうる塩、アセチルコリンエステラーゼ阻害剤及び製薬上許容しうる担体を含有する１日単位投与量医薬組成物も記載される。種々の場合において、１日単位投与量医薬組成物は、０．５（０．３、又は０．１）ｍｇ以下の（Ｒ）−７−クロロ−Ｎ−（キヌクリジン−３−イル）ベンゾ［ｂ］チオフェン−２−カルボキサミド又はその製薬上許容しうる塩を含有する。種々の場合において、１日単位投与量医薬組成物は、５、４、３、２、１、又は０．５ｍｇ以下のドネペジルを含有する。 1.0 mg or less of (R) -7-chloro-N- (quinuclidin-3-yl) benzo [b] thiophene-2-carboxamide or a pharmaceutically acceptable salt thereof, an acetylcholinesterase inhibitor and a pharmaceutically acceptable A daily unit dosage pharmaceutical composition containing a carrier is also described. In various cases, a daily unit dosage pharmaceutical composition comprises 0.5 (0.3 or 0.1) mg or less of (R) -7-chloro-N- (quinuclidin-3-yl) benzo [ b] contains thiophene-2-carboxamide or a pharmaceutically acceptable salt thereof. In various cases, a daily unit dosage pharmaceutical composition contains no more than 5, 4, 3, 2, 1, or 0.5 mg donepezil.
（Ｒ）−７−クロロ−Ｎ−（キヌクリジン−３−イル）ベンゾ［ｂ］チオフェン−２−カルボキサミド又はその製薬上許容しうる塩を含有する第１の単位投与量医薬組成物、及びアセチルコリンエステラーゼ阻害剤を含有する第２の単位投与量医薬組成物を含むパッケージを含む、包装された医薬品も記載される。 (R) -7-chloro-N- (quinuclidin-3-yl) benzo [b] thiophene-2-carboxamide or a first unit dose pharmaceutical composition containing a pharmaceutically acceptable salt thereof, and acetylcholinesterase A packaged medicament is also described, including a package comprising a second unit dose pharmaceutical composition containing an inhibitor.
別の態様において、患者は、アセチルコリンエステラーゼ阻害剤と組み合わせて、式Ｉ: In another embodiment, the patient is in combination with an acetylcholinesterase inhibitor of formula I:
（式中、
Ｒ１は１−アザビシクロ［２．２．２］オクト−３−イルを表し、
Ｒ２は水素又はＣ１−Ｃ６−アルキルを表し、
Ｒ３は水素、ハロゲン又はＣ１−Ｃ６−アルキルを表し、
Ａは酸素又は硫黄を表し、そして
Ｚはハロゲン、ホルミル、カルバモイル、シアノ、トリフルオロメチル、トリフルオロメトキシ、ニトロ、アミノ、ホルムアミド、アセトアミド、Ｃ１−Ｃ６−アルキル、Ｃ１−Ｃ６−アルコキシ（alkyoxy）、Ｃ１−Ｃ６−アルキルチオ、Ｃ１−Ｃ６−アルキルアミノ、ヘテロアリール−カルボニルアミノ、アリールカルボニルアミノ、Ｃ１−Ｃ４−アルキルスルホニルアミノ、ジ（アリールスルホニル）アミノ、Ｃ３−Ｃ６−シクロアルキルカルボニルメチル又はアミノ（ヒドロキシイミノ）メチルを表す）のアセチルコリンエステラーゼ阻害剤、又はその塩、その溶媒和物若しくはその塩の溶媒和物を用いて治療されうる。
(Where
R 1 represents 1-azabicyclo [2.2.2] oct-3-yl,
R 2 represents hydrogen or C1-C6-alkyl,
R 3 represents hydrogen, halogen or C1-C6-alkyl,
A represents oxygen or sulfur, and Z represents halogen, formyl, carbamoyl, cyano, trifluoromethyl, trifluoromethoxy, nitro, amino, formamide, acetamide, C1-C6-alkyl, C1-C6-alkoxy, C1-C6-alkylthio, C1-C6-alkylamino, heteroaryl-carbonylamino, arylcarbonylamino, C1-C4-alkylsulfonylamino, di (arylsulfonyl) amino, C3-C6-cycloalkylcarbonylmethyl or amino (hydroxy It can be treated with an acetylcholinesterase inhibitor of (Imino) methyl), or a salt, solvate or solvate thereof.
別の態様において、患者は、式Ｉ（式中、Ｒ２は水素であり、Ｒ３は水素であり、Ａは硫黄であり、そしてＺはハロゲン、ホルミル、カルバモイル、シアノ、トリフルオロメチル、トリフルオロメトキシ、ニトロ、アミノ、ホルムアミド、アセトアミド、Ｃ１−Ｃ６−アルキル、Ｃ１−Ｃ６−アルコキシ（alkyoxy）、Ｃ１−Ｃ６−アルキルチオ、Ｃ１−Ｃ６−アルキルアミノ、ヘテロアリール−カルボニルアミノ、アリールカルボニルアミノ、Ｃ１−Ｃ４−アルキルスルホニルアミノ、ジ（アリールスルホニル）アミノ、Ｃ３−Ｃ６−シクロアルキルカルボニルメチル又はアミノ（ヒドロキシイミノ）メチル（具体的にはハロゲン、シアノ、トリフルオロメチル、トリフルオロメトキシ、メチル、エチル、メトキシ、及びエトキシ；より具体的にはハロゲン又はシアノ、なおより具体的にはクロロ又はシアノ）を表す）の化合物を用いて治療される。 In another embodiment, the patient has Formula I wherein R 2 is hydrogen, R 3 is hydrogen, A is sulfur, and Z is halogen, formyl, carbamoyl, cyano, trifluoromethyl, trimethyl. Fluoromethoxy, nitro, amino, formamide, acetamide, C1-C6-alkyl, C1-C6-alkoxy, C1-C6-alkylthio, C1-C6-alkylamino, heteroaryl-carbonylamino, arylcarbonylamino, C1 -C4-alkylsulfonylamino, di (arylsulfonyl) amino, C3-C6-cycloalkylcarbonylmethyl or amino (hydroxyimino) methyl (specifically halogen, cyano, trifluoromethyl, trifluoromethoxy, methyl, ethyl, Methoxy and ethoxy; more specific To be treated with halogen or cyano, it noted compounds more specifically represents chloro or cyano)).
本明細書中に、１以上のアセチルコリンエステラーゼ阻害剤と組み合わせて（Ｒ）−７−クロロ−Ｎ−（キヌクリジン−３−イル）ベンゾ［ｂ］チオフェン−２−カルボキサミド又はその製薬上許容しうる塩を（例えば、以下の１日投与量で：３ ｍｇ、２．７０ｍｇ、２．５０ｍｇ、２．２５ｍｇ、２ｍｇ、１．７５ｍｇ、１．５０ｍｇ、１．２５ｍｇ、１ｍｇ、０．７ｍｇ、０．５ｍｇ、０．３ｍｇ、０．１ｍｇ、０．０３ｍｇ又は０．０１ｍｇ）含有する医薬組成物を投与することにより患者を治療する方法が記載される。該治療は、認知機能の１以上の面（facets）（例えば、視覚運動スキル、学習、遅延記憶、注意力、作業記憶、視覚学習、処理速度、ビジランス、言語学習、視覚運動機能、社会的認知、長期記憶、実行機能等）を改善しうる。患者は、（Ｒ）−７−クロロ−Ｎ−（キヌクリジン−３−イル）ベンゾ［ｂ］チオフェン−２−カルボキサミドの投与より先に一定期間、アセチルコリンエステラーゼ阻害剤を用いて治療されていることができる。例えば、患者は、少なくとも１週間、少なくとも１ヶ月間、少なくとも２ヶ月間、少なくとも３ヶ月間、少なくとも４ヶ月間、少なくとも６ヶ月間又は少なくとも１年間、アセチルコリンエステラーゼ阻害剤を用いて治療されていることができる。２つの薬剤は、同じ組成物中か又は２つの異なる組成物中で同時に投与されうる。また、これらの薬剤は異なる時間に投与されうる。 (R) -7-chloro-N- (quinuclidin-3-yl) benzo [b] thiophene-2-carboxamide or a pharmaceutically acceptable salt thereof in combination with one or more acetylcholinesterase inhibitors (E.g., at the following daily doses: 3 mg, 2.70 mg, 2.50 mg, 2.25 mg, 2 mg, 1.75 mg, 1.50 mg, 1.25 mg, 1 mg, 0.7 mg, 0.5 mg , 0.3 mg, 0.1 mg, 0.03 mg, or 0.01 mg) is described. The treatment includes one or more facets of cognitive function (eg, visual motor skills, learning, delayed memory, attention, working memory, visual learning, processing speed, vigilance, language learning, visual motor function, social cognition , Long-term memory, execution function, etc.). The patient may have been treated with an acetylcholinesterase inhibitor for a period of time prior to administration of (R) -7-chloro-N- (quinuclidin-3-yl) benzo [b] thiophene-2-carboxamide. it can. For example, the patient has been treated with an acetylcholinesterase inhibitor for at least 1 week, at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 6 months or at least 1 year. Can do. The two agents can be administered simultaneously in the same composition or in two different compositions. Also, these agents can be administered at different times.
本明細書中に、（Ｒ）−７−クロロ−Ｎ−（キヌクリジン−３−イル）ベンゾ［ｂ］チオフェン−２−カルボキサミド又はその製薬上許容しうる塩、及びアセチルコリンエステラーゼ阻害剤（例えば、タクリン、ドネペジル、リバスチグミン又はガランタミン）並びに製薬上許容しうる担体を含有する医薬組成物も記載される。 (R) -7-Chloro-N- (quinuclidin-3-yl) benzo [b] thiophene-2-carboxamide or a pharmaceutically acceptable salt thereof, and an acetylcholinesterase inhibitor (eg, tacrine) , Donepezil, rivastigmine or galantamine) and a pharmaceutically acceptable carrier are also described.
「投与量」は、患者に投与される原薬（active pharmaceutical ingredient）（ＡＰＩ）の量である。例えば、１ｍｇとは、各患者に１日あたり１ｍｇのＡＰＩが経口投与されたことを意味する。 “Dose” is the amount of active pharmaceutical ingredient (API) administered to a patient. For example, 1 mg means that 1 mg of API was orally administered to each patient per day.
「原薬」としては、（Ｒ）−７−クロロ−Ｎ−（キヌクリジン−３−イル）ベンゾ［ｂ］チオフェン−２−カルボキサミド塩酸塩、（Ｒ）−７−クロロ−Ｎ−（キヌクリジン−３−イル）ベンゾ［ｂ］チオフェン−２−カルボキサミド、（Ｒ）−７−クロロ−Ｎ−（キヌクリジン−３−イル）ベンゾ［ｂ］チオフェン−２−カルボキサミド塩酸塩一水和物及び（Ｒ）−７−クロロ−Ｎ−（キヌクリジン−３−イル）ベンゾ［ｂ］チオフェン−２−カルボキサミド塩酸塩溶媒和物、並びに式Ｉの化合物が挙げられる。 “Drug substance” includes (R) -7-chloro-N- (quinuclidin-3-yl) benzo [b] thiophene-2-carboxamide hydrochloride, (R) -7-chloro-N- (quinuclidine-3 -Yl) benzo [b] thiophene-2-carboxamide, (R) -7-chloro-N- (quinuclidin-3-yl) benzo [b] thiophene-2-carboxamide hydrochloride monohydrate and (R)- 7-chloro-N- (quinuclidin-3-yl) benzo [b] thiophene-2-carboxamide hydrochloride solvate, as well as compounds of formula I.
溶媒和物は、（Ｒ）−７−クロロ−Ｎ−（キヌクリジン−３−イル）ベンゾ［ｂ］チオフェン−２−カルボキサミド塩酸塩又は（Ｒ）−７−クロロ−Ｎ−（キヌクリジン−３−イル）ベンゾ［ｂ］チオフェン−２−カルボキサミドに対して化学量論比が０．１から１０分子の溶媒を表す。溶媒分子としては、水、メタノール、１，４−ジオキサン、エタノール、イソプロパノール又はアセトンが挙げられるがこれらに限定されない。場合によっては、水が好ましい溶媒和物である。 Solvates are (R) -7-chloro-N- (quinuclidin-3-yl) benzo [b] thiophene-2-carboxamide hydrochloride or (R) -7-chloro-N- (quinuclidin-3-yl). ) Represents a solvent having a stoichiometric ratio of 0.1 to 10 molecules with respect to benzo [b] thiophene-2-carboxamide. Solvent molecules include, but are not limited to water, methanol, 1,4-dioxane, ethanol, isopropanol, or acetone. In some cases, water is a preferred solvate.
ＡＤ患者に投与される（Ｒ）−７−クロロ−Ｎ−（キヌクリジン−３−イル）ベンゾ［ｂ］チオフェン−２−カルボキサミド及びドネペジル又はリバスチグミン
（Ｒ）−７−クロロ−Ｎ−（キヌクリジン−３−イル）ベンゾ［ｂ］チオフェン−２−カルボキサミド塩酸塩の安全性及び有効性を、安定なドネペジル（５又は１０ｍｇ／日）又はリバスチグミン（１日２回投与量として６〜１２ｍｇ／日で投与される（即ち、投与量あたり３又は６ｍｇ））に関して、４８名の軽度から中等度のＡＤ患者（年齢６０〜８０歳）の第１ｂ相試験において評価した。
(R) -7-Chloro-N- (quinuclidin-3-yl) benzo [b] thiophene-2-carboxamide and donepezil or rivastigmine (R) -7-chloro-N- (quinuclidine-3 ) administered to AD patients -Il) The safety and efficacy of benzo [b] thiophene-2-carboxamide hydrochloride is administered with stable donepezil (5 or 10 mg / day) or rivastigmine (twice daily dose 6-12 mg / day) (Ie 3 or 6 mg per dose)) in a phase 1b study of 48 mild to moderate AD patients (age 60-80 years).
偽薬又は２つの異なる投与量の（Ｒ）−７−クロロ−Ｎ−（キヌクリジン−３−イル）ベンゾ［ｂ］チオフェン−２−カルボキサミド（０．３又は１．０ｍｇ／ｄ）を２８日間、患者に投与した。安全性は、有害事象、ＥＣＧ、及び臨床検査測定値によって評価した。認知作用は、ＣｏｇＳｔａｔｅのコンピュータ化された認知機能試験及びＮＴＢスケールの一部（カテゴリー流暢性（category fluency）、トレイル（Trails）Ａ及びＢ）によって測定した。この分析の結果を図１に示す。 Patients who received placebo or two different doses of (R) -7-chloro-N- (quinuclidin-3-yl) benzo [b] thiophene-2-carboxamide (0.3 or 1.0 mg / d) for 28 days Administered. Safety was assessed by adverse events, ECG, and laboratory measurements. Cognitive effects were measured by CogState's computerized cognitive function tests and part of the NTB scale (category fluency, Trails A and B). The result of this analysis is shown in FIG.
偽薬の患者に対して、治療した患者においてより高頻度で報告された顕著な有害事象は無く、（Ｒ）−７−クロロ−Ｎ−（キヌクリジン−３−イル）ベンゾ［ｂ］チオフェン−２−カルボキサミドは安全であり、良好な耐容性を示すように見えた；重篤な有害事象（ＳＡＥ）は報告されなかった。ドネペジル又はリバスチグミンに加えて（Ｒ）−７−クロロ−Ｎ−（キヌクリジン−３−イル）ベンゾ［ｂ］チオフェン−２−カルボキサミドにさらされた対象は、認知機能（主に非言語学習、記憶、及び実行機能の領域）の増進を示した。 There were no significant adverse events reported more frequently in treated patients versus placebo patients, and (R) -7-chloro-N- (quinuclidin-3-yl) benzo [b] thiophene-2- Carboxamide appeared to be safe and well tolerated; no serious adverse events (SAE) were reported. Subjects exposed to (R) -7-chloro-N- (quinuclidin-3-yl) benzo [b] thiophene-2-carboxamide in addition to donepezil or rivastigmine have cognitive function (mainly non-language learning, memory, And execution function area).
無症候性投与量での（Ｒ）−クロロ−Ｎ−（キヌクリジン−３−イル）ベンゾ［ｂ］チオフェン−２−カルボキサミド及びドネペジルは記憶を改善する(R) -Chloro-N- (quinuclidin-3-yl) benzo [b] thiophene-2-carboxamide and donepezil at asymptomatic dose improves memory
以下に記載する研究では、５月齢のオスのウィスターラットにおける物体認識タスクにおいて、ムスカリンアンタゴニストであるスコポラミンによって誘導される短期記憶障害への、α７ニコチン性受容体アゴニスト（Ｒ）−７−クロロ−Ｎ−（キヌクリジン−３−イル）ベンゾ［ｂ］チオフェン−２−カルボキサミド及びＡＣｈＥ阻害剤ドネペジルの閾値下投与量の影響を調べた。物体認識タスクは、（物体）情報の記憶への固定の評価を可能にする（Ennaceur and Delacour, 1988; Prickaerts et al., 1997）。このタスクにおいては、ラットに２つの試験（trials）を与える。第一の試験においては、ラットを２つの同一の物体が置かれた活動領域（arena）に入れる。通常、ラット（rate）は２つの物体を一定時間点検するであろう。一定の遅延時間の後、ラットに第二の試験を与える。この試験においては、ラットを、同じ活動領域であるが一方の物体が新規の物体に置き換えられている活動領域に再び置く。第一の試験と同様に、ラットは２つの物体を再び探索する。ラットが２つの物体を探索するのに異なる時間をかけたか否かを決定するために、各物体を探索する時間を記録する。この採点法に基づき、記憶能力を決定することができる。 In the study described below, an α7 nicotinic receptor agonist (R) -7-chloro-N to short-term memory impairment induced by the muscarinic antagonist scopolamine in an object recognition task in 5 month old male Wistar rats. The effects of subthreshold doses of-(quinuclidin-3-yl) benzo [b] thiophene-2-carboxamide and the AChE inhibitor donepezil were examined. The object recognition task allows a fixed assessment of (object) information to memory (Ennaceur and Delacour, 1988; Prickaerts et al., 1997). In this task, rats are given two trials. In the first test, rats are placed in an arena where two identical objects are placed. Usually, a rat will check two objects for a period of time. Rats are given a second test after a certain delay time. In this test, the rat is again placed in the same active area but in an active area where one object has been replaced with a new object. As in the first test, the rat searches for two objects again. To determine whether the rat has spent different times searching for two objects, the time to search for each object is recorded. Based on this scoring method, memory ability can be determined.
いくつかの研究は、１時間の遅延時間が第一の試験と第二の試験の間に挿入される場合、ウィスターラットが優れた物体記憶能力を示すことを示している。しかしながら、２４時間の遅延時間が使用される場合、ラットは第二の試験において新規の物体と見慣れた物体とを識別せず、このことはラットが見慣れた物体（即ち、第一の試験及び第二の試験の両方において提示された物体）を記憶しないことを示している。６時間の遅延時間を使用すると、識別能力は１時間の遅延時間の場合の能力と２４時間の遅延時間の場合の能力との間であり、このことはこのタスクにおける遅延時間依存性の忘却を示唆している。 Some studies have shown that Wistar rats show excellent object memory ability when a one hour delay is inserted between the first and second tests. However, if a 24 hour delay is used, the rat does not distinguish between new and familiar objects in the second test, which means that the rat is familiar with the objects (ie, the first and second tests). The object presented in both tests is not remembered. Using a delay time of 6 hours, the discriminatory ability is between the ability for the 1 hour delay time and the ability for the 24 hour delay time, which reduces the delay time-dependent forgetting in this task. Suggests.
以前の研究は、０．３ｍｇ／ｋｇの（Ｒ）−７−クロロ−Ｎ−（キヌクリジン−３−イル）ベンゾ［ｂ］チオフェン−２−カルボキサミド（p.o.）がムスカリンアンタゴニストであるスコポラミン（０．１ｍｇ／ｋｇ、i.p.）によって誘導される物体記憶障害を完全に減衰させるのに対して、０．０３ｍｇ／ｋｇの投与量は効果がないことを見出した。０．３ｍｇ／ｋｇの投与量のドネペジル（p.o.）がスコポラミン誘導性物体記憶障害を減衰させるのに対して、０．１ｍｇ／ｋｇのドネペジルは効果がないことも見出された。予備的研究においては、驚いたことに、この閾値下投与量のドネペジルと閾値下投与量の（Ｒ）−クロロ−Ｎ−（キヌクリジン−３−イル）ベンゾ［ｂ］チオフェン−２−カルボキサミドとの併用投与（これらはいずれも、単独で閾値下投与量で与えられた場合、能力に影響しない）が、スコポラミンによって誘導された物体記憶障害を有するラットにおいて記憶能力を増強することが見出された。このことは、認知機能障害に対する両化合物間の相加相乗効果を示唆する。 Previous studies have shown that 0.3 mg / kg (R) -7-chloro-N- (quinuclidin-3-yl) benzo [b] thiophene-2-carboxamide (po) is a muscarinic antagonist (0.1 mg The dose of 0.03 mg / kg was found to be ineffective while completely attenuating the object memory impairment induced by / kg, ip). It was also found that a dose of 0.3 mg / kg donepezil (p.o.) attenuated scopolamine-induced object memory impairment, whereas 0.1 mg / kg donepezil was ineffective. In a preliminary study, surprisingly, this subthreshold dose of donepezil and a subthreshold dose of (R) -chloro-N- (quinuclidin-3-yl) benzo [b] thiophene-2-carboxamide Combination administration (none of which affects performance when given alone at sub-threshold doses) was found to enhance memory performance in rats with scopolamine-induced object memory impairment . This suggests an additive synergistic effect between both compounds on cognitive impairment.
本研究において、学習試験の３０分前に、ムスカリン性受容体アンタゴニストであるスコポラミンをラットに注射した（０．１ｍｇ／ｋｇ、i.p.投与）。スコポラミンによる処置の後、ラットは学習試験の１時間後には物体の記憶を示さないであろう。閾値下投与量の（Ｒ）−７−クロロ−Ｎ−（キヌクリジン−３−イル）ベンゾ［ｂ］チオフェン−２−カルボキサミド（０．０３ｍｇ／ｋｇ、p.o.投与）及びドネペジル（０．１ｍｇ／ｋｇ、p.o.投与）の組み合わせがスコポラミン誘導性物体記憶障害を減衰しうるか否かを検討した。全ての薬物を第一の試験の３０分前に与えた。 In this study, rats were injected with scopolamine, a muscarinic receptor antagonist, 30 minutes prior to the learning test (0.1 mg / kg, i.p. administration). After treatment with scopolamine, rats will not show memory of objects after 1 hour of the learning test. Sub-threshold doses of (R) -7-chloro-N- (quinuclidin-3-yl) benzo [b] thiophene-2-carboxamide (0.03 mg / kg, po administration) and donepezil (0.1 mg / kg, We investigated whether a combination of po administration) could attenuate scopolamine-induced object memory impairment. All drugs were given 30 minutes before the first test.
全ての実験手順は、動物実験のためのマーストリヒト大学の地方倫理委員会よって承認され、政府のガイドラインを満たした。２４匹の５月齢のオスのウィスターラット（Harlan、The Netherlands）を使用した（平均体重：４６５ｇ）。これらの２４匹の動物のうち、２３匹の動物のみを最終的な分析に含めたが、これは１匹のラットが逃げ続けたことに起因した。これらの動物を、空調された部屋（約２０℃）の中で、標準の３型マクロロンケージ内、おが屑の床敷の上に個別に収容した。それらを１２／１２時間の明暗周期（１９時から７時まで点灯）下で維持し、飼料及び水を自由摂取させた。ラットは、該動物を試験するのと同じ部屋に収容した。ラジオ（静かにかけた）で室内に背景雑音を提供した。全ての試験を９時から最長１８時までの間に行なった。 All experimental procedures were approved by the local ethics committee at Maastricht University for animal experiments and met government guidelines. Twenty-four 5 month old male Wistar rats (Harlan, The Netherlands) were used (average body weight: 465 g). Of these 24 animals, only 23 animals were included in the final analysis due to the continued escape of one rat. The animals were housed individually in an air-conditioned room (approximately 20 ° C.) in a standard type 3 macrolon cage on a sawdust floor. They were maintained under a 12/12 hour light-dark cycle (lights on from 19:00 to 7:00) and allowed free access to feed and water. Rats were housed in the same room where the animals were tested. Provided background noise in the room by radio (slowly). All tests were performed between 9 o'clock and up to 18 o'clock.
以前のスコポラミンの用量反応試験に基づき、０．１ｍｇ／ｋｇの投与量が記憶障害を誘導するために最も効果的な投与量であると決定した。スコポラミン臭化水素酸塩は毎日調製し、生理食塩水に溶解させた。試験１の３０分前に、スコポラミンをi.p.投与した（注射量１ｍｌ／ｋｇ）。ＥＶＰ−６１２４はＨ２Ｏに溶解させた。溶液は毎日調製し、０．０３ｍｇ／ｋｇ p.o.の投与量で試験した（注射量２ｍｌ／ｋｇ）。投与は常に、スコポラミンの直後、試験１の３０分前に行なった。ドネペジルは生理食塩水に溶解させた。溶液は毎日調製し、０．１ｍｇ／ｋｇ p.o.の投与量で試験した（注射量２ｍｌ／ｋｇ）。投与は常に、（Ｒ）−７−クロロ−Ｎ−（キヌクリジン−３−イル）ベンゾ［ｂ］チオフェン−２−カルボキサミドの直後、試験１の３０分前に行なった。
Based on previous dose response studies of scopolamine, the 0.1 mg / kg dose was determined to be the most effective dose to induce memory impairment. Scopolamine hydrobromide was prepared daily and dissolved in saline. 30 minutes before Test 1, scopolamine was administered ip (injection volume 1 ml / kg). EVP-6124 was dissolved in H 2 O. Solutions were prepared daily and tested at a dose of 0.03 mg / kg po (
ビヒクル及びスコポラミン条件を最初に試験した。続いてドネペジル、（Ｒ）−７−クロロ−Ｎ−（キヌクリジン−３−イル）ベンゾ［ｂ］チオフェン−２−カルボキサミド及び両方の組み合わせを試験した（試験日あたり条件ごとにｎ＝８）。全てのラットを各投与量条件により１回処置した。しかしながら、装置から飛び出し続けたことに起因して１匹のラットを試験から除外したため、ｎ＝２３である。実験者は、試験される条件／薬物を知らなかった。 Vehicle and scopolamine conditions were first tested. Subsequently, donepezil, (R) -7-chloro-N- (quinuclidin-3-yl) benzo [b] thiophene-2-carboxamide and a combination of both were tested (n = 8 per condition per test day). All rats were treated once with each dose condition. However, n = 23 because one rat was excluded from the study due to continuing to jump out of the device. The experimenter did not know the condition / drug to be tested.
物体認識試験は、他の場所（Ennaceur and Delacour、1988）に記載されたように実施した。装置は、直径８３ｃｍの円形の活動領域から構成された。高さ４０ｃｍの壁の半分は灰色のポリ塩化ビニル製、残りの半分は透明のポリ塩化ビニル製であった。光の強さは装置の様々な部分において等しかった。２つの物体を、灰色の壁から約１０ｃｍ離れた対称の位置に置いた。各物体は三つ同じものが利用可能であった。これらの物体は以下であった：１）上に真ちゅう製のカラーを有する灰色のポリ塩化ビニルの底面（最大直径１８ｃｍ）から構成される円錐（全高１６ｃｍ）、２）水で満たした標準的な１ｌの褐色の透明ガラスボトル（直径１０ｃｍ、高さ２２ｃｍ）、３）２つの穴（直径１．９ｃｍ）を有する重い金属の立方体（１０．０ｘ５．０ｘ７．５ｃｍ）、及び４）先細りの上面を有する重いアルミニウムの立方体（１３．０ｘ８．０ｘ８．０ｃｍ）。ラットはこれらの物体を動かすことはできなかった。赤色の蛍光灯及び電球が、装置の床の上で約２０ルクスの一定の照明を提供した。 Object recognition tests were performed as described elsewhere (Ennaceur and Delacour, 1988). The device consisted of a circular active area with a diameter of 83 cm. Half of the 40 cm high wall was made of gray polyvinyl chloride and the other half was made of transparent polyvinyl chloride. The light intensity was equal in different parts of the device. The two objects were placed in a symmetrical position about 10 cm away from the gray wall. Three identical objects were available. These objects were: 1) a cone (total height 16 cm) composed of a gray polyvinyl chloride bottom surface (maximum diameter 18 cm) with a brass collar on top, 2) a standard filled with water 1 l brown clear glass bottle (diameter 10 cm, height 22 cm), 3) heavy metal cube with two holes (diameter 1.9 cm) (10.0 x 5.0 x 7.5 cm), and 4) taper top Heavy aluminum cube with 13.0 x 8.0 x 8.0 cm. Rats were unable to move these objects. Red fluorescent lamps and bulbs provided a constant illumination of about 20 lux on the floor of the device.
試験セッションは２つの試験から構成された。各試験の期間は３分であった。第一の試験（Ｔ１）の間、装置は２つの同一の物体（見本）を含んでいた。ラットは常に、前部の（透明な）区域の中央に、壁に向けて装置内に置いた。第１の探索期間の後、ラットをそのホームケージに戻した。続いて、所定の遅延間隔の後、ラットを第二の試験（Ｔ２）のために装置に戻したが、今度は２つの非類似の物体（見慣れたもの（見本）及び新しいもの）を用いた。Ｔ１及びＴ２の間に各物体を探索するのに費やした時間を、パーソナルコンピューターを用いて手作業で記録した。 The test session consisted of two tests. The duration of each test was 3 minutes. During the first test (T1), the device contained two identical objects (swatches). Rats were always placed in the apparatus, facing the wall, in the middle of the front (transparent) area. After the first exploration period, the rat was returned to its home cage. Subsequently, after a predetermined delay interval, the rat was returned to the device for a second test (T2), but this time with two dissimilar objects (familiar (sample) and new). . The time spent searching for each object during T1 and T2 was recorded manually using a personal computer.
探索は以下のように定義した：２ｃｍ以下の距離で物体に鼻を向けること及び／又は鼻で物体に触れること。物体の上に座ることは、探索行動とはみなさなかった。嗅覚的痕跡の存在を排除するために、物体を常に徹底的に洗浄した。物体の全ての組み合わせ及び位置をバランスの取れた様式で使用して、特定の位置又は物体に対する嗜好性に起因する潜在的なバイアスを低減させた。 The search was defined as follows: directing the nose to the object and / or touching the object with the nose at a distance of 2 cm or less. Sitting on an object was not considered exploratory behavior. To eliminate the presence of olfactory traces, the object was always thoroughly washed. All combinations and positions of objects were used in a balanced manner to reduce potential bias due to preference for specific positions or objects.
いくつかの研究は、１時間の遅延時間が第一の試験と第二の試験との間に挿入される場合、ウィスターラットが優れた物体記憶能力を示すことを示している。しかしながら、２４時間の遅延時間が使用される場合、ラットは第二の試験において新規のものと見慣れたものとを識別せず、このことはラットが第一の試験において提示された物体を記憶しないことを示している。６時間の遅延時間を使用すると、識別能力は１時間の遅延時間の場合の能力と２４時間の遅延時間の場合の能力との間であり、このことはこのタスクにおける遅延時間依存性の忘却を示唆している。この研究においては、１時間の間隔を使用する。 Some studies have shown that Wistar rats exhibit excellent object memory ability when a one hour delay is inserted between the first and second tests. However, when a 24 hour delay is used, the rat does not distinguish between new and familiar in the second test, which does not remember the object presented in the first test. It is shown that. Using a delay time of 6 hours, the discriminatory ability is between the ability for the 1 hour delay time and the ability for the 24 hour delay time, which reduces the delay time-dependent forgetting in this task. Suggests. In this study, a one hour interval is used.
２週間、動物に毎日手を触れ、２日間で手順に順応させた（即ち、動物に毎日２回３分間、装置（いかなる物体もない）を探索させた）。次いで、ラットが安定した識別能力（即ち１時間間隔ではよく識別し、２４時間間隔では識別しないこと）を示すまで、試験、並びに第一の試験の３０分前の生理食塩水注射によるi.p.注射及びp.o.注射（それぞれ１．０ｍｌ／ｋｇ及び２．０ｍｌ／ｋｇ）に順応させた。次に、コントロールセッション（ビヒクル及びスコポラミンを試験した）。続いて、薬物（Ｒ）−７−クロロ−Ｎ−（キヌクリジン−３−イル）ベンゾ［ｂ］チオフェン−２−カルボキサミド（０．０３ｍｇ／ｋｇ）及びドネペジル（０．１ｍｇ／ｋｇ）の試験を開始した。化合物セッション間に十分なウォッシュアウト期間を置くために、化合物／ビヒクルは常に月曜日、水曜日及び金曜日（又は火曜日及び木曜日）に試験した。 The animals were touched daily for 2 weeks and allowed to acclimate to the procedure in 2 days (ie, the animals were probed for devices (no objects) twice a day for 3 minutes). The test and then the ip injection with a saline injection 30 minutes before the first test and until the rat shows a stable discriminating ability (i.e. well identified at 1 hour interval but not at 24 hour interval) Adapted to po injections (1.0 ml / kg and 2.0 ml / kg, respectively). Next, a control session (vehicle and scopolamine were tested). Subsequently, drug (R) -7-chloro-N- (quinuclidin-3-yl) benzo [b] thiophene-2-carboxamide (0.03 mg / kg) and donepezil (0.1 mg / kg) started did. The compound / vehicle was always tested on Mondays, Wednesdays and Fridays (or Tuesdays and Thursdays) to allow for a sufficient washout period between compound sessions.
基本的な尺度は、ラットがＴ１及びＴ２の間に物体を探索するのに費やした時間であった。２つの同一の見本を探索するのに費やした時間は、「ａ１」及び「ａ２」によって表される。Ｔ２において見本及び新しい物体を探索するのに費やした時間は、それぞれ「ａ」及び「ｂ」によって表される。以下の変数を計算した：ｅ１＝ａ１＋ａ２、ｅ２＝ａ＋ｂ、及びｄ２＝（ｂ−ａ）／ｅ２（表１を参照のこと）。ｅ１及びｅ２は、それぞれＴ１及びＴ２中の両方の物体の総探索時間の尺度である。ｄ２は、探索活動（ｅ２）に対して補正した識別の相対的尺度である。従って、同様の間隔での同様の処置による実験間では、ｄ２指数に差異はないはずである。本実験においては５つの条件があり、各ラットを各条件に供した： The basic measure was the time that the rat spent searching for objects between T1 and T2. The time spent searching for two identical samples is represented by “a1” and “a2”. The time spent searching for a sample and a new object at T2 is represented by “a” and “b”, respectively. The following variables were calculated: e1 = a1 + a2, e2 = a + b, and d2 = (b−a) / e2 (see Table 1). e1 and e2 are measures of the total search time for both objects in T1 and T2, respectively. d2 is a relative measure of discrimination corrected for search activity (e2). Therefore, there should be no difference in d2 index between experiments with similar treatments at similar intervals. There are five conditions in this experiment and each rat was subjected to each condition:
１）ビヒクル（スコポラミン）、ビヒクル（ドネペジル）＆ビヒクル（（Ｒ）−７−クロロ−Ｎ−（キヌクリジン−３−イル）ベンゾ［ｂ］チオフェン−２−カルボキサミド）
２）スコポラミン、ビヒクル（ドネペジル）＆ビヒクル（（Ｒ）−７−クロロ−Ｎ−（キヌクリジン−３−イル）ベンゾ［ｂ］チオフェン−２−カルボキサミド）
３）スコポラミン、ドネペジル＆ビヒクル（（Ｒ）−７−クロロ−Ｎ−（キヌクリジン−３−イル）ベンゾ［ｂ］チオフェン−２−カルボキサミド）
４）スコポラミン、ビヒクル（ドネペジル）＆（Ｒ）−７−クロロ−Ｎ−（キヌクリジン−３−イル）ベンゾ［ｂ］チオフェン−２−カルボキサミド
５）スコポラミン、ドネペジル ＆（Ｒ）−７−クロロ−Ｎ−（キヌクリジン−３−イル）ベンゾ［ｂ］チオフェン−２−カルボキサミド
1) Vehicle (scopolamine), vehicle (donepezil) & vehicle ((R) -7-chloro-N- (quinuclidin-3-yl) benzo [b] thiophene-2-carboxamide)
2) Scopolamine, vehicle (donepezil) & vehicle ((R) -7-chloro-N- (quinuclidin-3-yl) benzo [b] thiophene-2-carboxamide)
3) Scopolamine, donepezil & vehicle ((R) -7-chloro-N- (quinuclidin-3-yl) benzo [b] thiophene-2-carboxamide)
4) Scopolamine, vehicle (donepezil) & (R) -7-chloro-N- (quinuclidin-3-yl) benzo [b] thiophene-2-carboxamide 5) scopolamine, donepezil & (R) -7-chloro-N -(Quinuclidin-3-yl) benzo [b] thiophene-2-carboxamide
ｄ２がゼロとは異なるか否かを処置条件ごとに評価するために、１サンプルｔ統計（t-statistics）を行なった。しかしながら、分散なしでのｄ２の値と値ゼロとの比較は、認識を分析するための最も適切な方法ではないかもしれない（タイプＩエラーをおかす危険性の増加）。従って、効果を被験者内（反復測定）ＡＮＯＶＡによっても評価した。条件間で有意差がある場合に備えて、ボンフェローニの補正を伴う事後解析を行なった。 To evaluate whether d2 is different from zero for each treatment condition, one sample t-statistics was performed. However, comparing the value of d2 without variance with the value zero may not be the most appropriate way to analyze recognition (increased risk of making type I errors). Therefore, the effect was also evaluated by within-subject (repeated measurement) ANOVA. A post hoc analysis with Bonferroni correction was performed in case there was a significant difference between conditions.
Ｔ１の３０分前のＥＶＰ−６１２４及びドネペジル処置の結果を表２にまとめる。Ｔ１における探索のレベルにおいて、処置条件間で差異は見出されなかった（ｅ１：Ｆ（４、８８）＝１．１３８、n.s.）。Ｔ２においても、Ｔ２における探索のレベルにおいて、処置条件間で差異は無かった（ｅ２：Ｆ（４、８８）＝０．８８８、n.s.）。 The results of EVP-6124 and donepezil treatment 30 minutes before T1 are summarized in Table 2. No difference was found between treatment conditions at the level of exploration at T1 (e1: F (4,88) = 1.138, n.s.). Also at T2, there was no difference between treatment conditions at the level of search in T2 (e2: F (4,88) = 0.888, n.s.).
１サンプルｔ検定により、併用条件及びビヒクル条件のｄ２値がゼロとは異なることが示された（表２Ｂを参照のこと）。これは、スコポラミン、（Ｒ）−７−クロロ−Ｎ−（キヌクリジン−３−イル）ベンゾ［ｂ］チオフェン−２−カルボキサミド及びドネペジルを別々に投与した条件（差異を示さなかった）とは対照的である。（Ｒ）−７−クロロ−Ｎ−（キヌクリジン−３−イル）ベンゾ［ｂ］チオフェン−２−カルボキサミド及びドネペジル処置の相対的識別指数ｄ２への影響を図１に図示する。群間で比較した場合、ｄ２指数について差異が見出された（Ｆ（４、８８）＝８．１８１、Ｐ＜０．００１）。ｄ２は、スコポラミン条件、（Ｒ）−７−クロロ−Ｎ−（キヌクリジン−３−イル）ベンゾ［ｂ］チオフェン−２−カルボキサミド条件及びドネペジル条件よりも、併用条件及びビヒクル条件において、より高かった（ボンフェローニｔ検定；図２を参照のこと）。 A one sample t-test showed that the combined and vehicle conditions d2 values were different from zero (see Table 2B). This is in contrast to conditions where scopolamine, (R) -7-chloro-N- (quinuclidin-3-yl) benzo [b] thiophene-2-carboxamide and donepezil were administered separately (no difference was shown). It is. The effect of (R) -7-chloro-N- (quinuclidin-3-yl) benzo [b] thiophene-2-carboxamide and donepezil treatment on the relative discrimination index d2 is illustrated in FIG. Differences were found for the d2 index when compared between groups (F (4,88) = 8.181, P <0.001). d2 was higher in the combination and vehicle conditions than in the scopolamine conditions, (R) -7-chloro-N- (quinuclidin-3-yl) benzo [b] thiophene-2-carboxamide conditions and donepezil conditions ( Bonferroni t test; see FIG. 2).
スコポラミン投与（i.p.）後の、併用された閾値下投与量の薬物（Ｒ）−７−クロロ−Ｎ−（キヌクリジン−３−イル）ベンゾ［ｂ］チオフェン−２−カルボキサミド（p.o.で与えた）及びドネペジル（p.o.）の認知機能増進効果の評価のために、１ｈの遅延間隔を使用した。対照のビヒクル条件において、ラットがそのような間隔の後に見慣れた物体を記憶していることが見出された。これは、スコポラミン（０．１ｍｇ／ｋｇ）条件（見慣れた物体の記憶はもはや見出されなかった）とは対照的である。本研究において、薬物試験に使用するスコポラミンの投与量は、動物の探索活動に影響しなかった。 Combined subthreshold dose of drug (R) -7-chloro-N- (quinuclidin-3-yl) benzo [b] thiophene-2-carboxamide (given in po) after scopolamine administration (ip) and A delay interval of 1 h was used to evaluate the effect of donepezil (po) on enhancing cognitive function. In control vehicle conditions, it was found that rats remembered familiar objects after such intervals. This is in contrast to the scopolamine (0.1 mg / kg) condition (a familiar object memory was no longer found). In this study, the dose of scopolamine used for drug testing did not affect animal exploration activities.
（Ｒ）−７−クロロ−Ｎ−（キヌクリジン−３−イル）ベンゾ［ｂ］チオフェン−２−カルボキサミドもドネペジルも、探索行動を変化させなかった。相対的識別指数ｄ２は、探索活動における変化（これらは本研究においては観察されなかったが）を補正する。更にこれは、ｗｉｔｈｉｎ分析（即ちゼロとの比較）で物体認識へのわずかな影響を検出できるため、信頼できる尺度である。ドネペジル条件のｄ２、並びに（Ｒ）−７−クロロ−Ｎ−（キヌクリジン−３−イル）ベンゾ［ｂ］チオフェン−２−カルボキサミド条件のｄ２は、ゼロと異ならなかった。同様に、ｂｅｔｗｅｅｎ分析（即ちスコポラミン単独で処置した動物との比較）は、閾値下投与量のＥＶＰ−６１２４（０．０３ｍｇ／ｋｇ）及びドネペジル（０．１ｍｇ／ｋｇ）が、別々に与えられた場合には、動物の記憶を改善しないことを示した。これは、併用条件（一緒に与えた閾値下投与量の（Ｒ）−７−クロロ−Ｎ−（キヌクリジン−３−イル）ベンゾ［ｂ］チオフェン−２−カルボキサミド及びドネペジルがスコポラミンによって引き起こされる物体記憶障害を完全に改善した）とは対照的である。 Neither (R) -7-chloro-N- (quinuclidin-3-yl) benzo [b] thiophene-2-carboxamide nor donepezil altered the exploratory behavior. The relative discrimination index d2 corrects for changes in exploratory activity, although these were not observed in this study. In addition, this is a reliable measure because within analysis (ie, comparison with zero) can detect minor effects on object recognition. The d2 of donepezil conditions and the d2 of (R) -7-chloro-N- (quinuclidin-3-yl) benzo [b] thiophene-2-carboxamide conditions were not different from zero. Similarly, between analysis (ie, comparison with animals treated with scopolamine alone) provided subthreshold doses of EVP-6124 (0.03 mg / kg) and donepezil (0.1 mg / kg) separately. In some cases, it showed no improvement in animal memory. This is because the combination conditions (sub-dose (R) -7-chloro-N- (quinuclidin-3-yl) benzo [b] thiophene-2-carboxamide and donepezil given together are the body memories caused by scopolamine. This is in contrast to the complete improvement of the disability.
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Prickaerts, J., Steinbusch, H.W.M., Smits, J.F.M., De Vente, J., 1997. Possible role of nitric oxide-cyclic GMP pathway in object recognition memory: Effects of 7-nitroindazole and zaprinast. Eur. J. Pharmacol. 337, 125-136.
Prickaerts, J., Sik, A., van Staveren, W.C., Koopmans, G., Steinbusch, H.W., van der Staay, F.J., de Vente, J., Blokland, A., 2004. Phosphodiesterase type 5 inhibition improves early memory consolidation of object information. Neurochem Int. 45, 915-928.
Prickaerts, J., Sik, A., van der Staay, F.J., de Vente, J., Blokland, A., 2005. Dissociable effects of acetylcholinesterase inhibitors and phosphodiesterase type 5 inhibitors on object recognition memory: acquisition versus consolidation. Psychopharmacology 177, 381-390.
本発明によれば、以下の態様が提供される。
［項１］
（Ｒ）−７−クロロ−Ｎ−（キヌクリジン−３−イル）ベンゾ［ｂ］チオフェン−２−カルボキサミド又はその製薬上許容しうる塩、及びアセチルコリンエステラーゼ阻害剤を患者に投与することを含む、認知機能を改善する方法。
［項２］
患者がアルツハイマー病又はプレアルツハイマー病と診断されている、項１記載の方法。
［項３］
患者が軽度から中等度のアルツハイマー病と診断されている、項１記載の方法。
［項４］
患者が中等度から重度のアルツハイマー病と診断されている、項１記載の方法。
［項５］
アセチルコリンエステラーゼ阻害剤がタクリン、ドネペジル、リバスチグミン及びガランタミンから選択される、前述のいずれかの項に記載の方法。
［項６］
アセチルコリンエステラーゼ阻害剤がドネペジル、リバスチグミン及びガランタミンから選択される、項５記載の方法。
［項７］
アセチルコリンエステラーゼ阻害剤がドネペジル及びリバスチグミンから選択される、項５記載の方法。
［項８］
患者が、（Ｒ）−７−クロロ−Ｎ−（キヌクリジン−３−イル）ベンゾ［ｂ］チオフェン−２−カルボキサミド又はその製薬上許容しうる塩を投与されるより先に一定期間アセチルコリンエステラーゼ阻害剤を投与されている、前述のいずれかの項に記載の方法。
［項９］
先の投与が少なくとも１ヶ月間である、項８記載の方法。
［項１０］
先の投与が少なくとも３ヶ月間である、項９記載の方法。
［項１１］
先の投与が少なくとも６ヶ月間である、項１０記載の方法。
［項１２］
以下の１以上を改善する、前述のいずれかの項に記載の方法：学習、遅延記憶、注意力、作業記憶、視覚学習、処理速度、ビジランス、言語学習、視覚運動機能、社会的認知、長期記憶又は実行機能。
［項１３］
（Ｒ）−７−クロロ−Ｎ−（キヌクリジン−３−イル）ベンゾ［ｂ］チオフェン−２−カルボキサミド又はその製薬上許容しうる塩、及びアセチルコリンエステラーゼ阻害剤の一方又は両方が無症候性投与量で投与される、項１記載の方法。
［項１４］
（Ｒ）−７−クロロ−Ｎ−（キヌクリジン−３−イル）ベンゾ［ｂ］チオフェン−２−カルボキサミド又はその製薬上許容しうる塩が１．０ｍｇ未満／日で経口投与される、項１３記載の方法。
［項１５］
（Ｒ）−７−クロロ−Ｎ−（キヌクリジン−３−イル）ベンゾ［ｂ］チオフェン−２−カルボキサミド又はその製薬上許容しうる塩が０．５ｍｇ未満／日で経口投与される、項１３記載の方法。
［項１６］
（Ｒ）−７−クロロ−Ｎ−（キヌクリジン−３−イル）ベンゾ［ｂ］チオフェン−２−カルボキサミド又はその製薬上許容しうる塩が０．３ｍｇ未満／日で経口投与される、項１３記載の方法。
［項１７］
（Ｒ）−７−クロロ−Ｎ−（キヌクリジン−３−イル）ベンゾ［ｂ］チオフェン−２−カルボキサミド又はその製薬上許容しうる塩が０．１ｍｇ未満／日で経口投与される、項１３記載の方法。
［項１８］
アセチルコリンエステラーゼ阻害剤がドネペジルであり、且つ５ｍｇ未満／日で経口投与される、項１３記載の方法。
［項１９］
アセチルコリンエステラーゼ阻害剤がドネペジルであり、且つ４．５ｍｇ／日又はそれ以下で経口投与される、項１３記載の方法。
［項２０］
アセチルコリンエステラーゼ阻害剤がドネペジルであり、且つ４．０ｍｇ／日又はそれ以下で経口投与される、項１３記載の方法。
［項２１］
アセチルコリンエステラーゼ阻害剤がドネペジルであり、且つ２．５ｍｇ／日又はそれ以下で経口投与される、項１３記載の方法。
［項２２］
アセチルコリンエステラーゼ阻害剤がドネペジルであり、且つ１．５ｍｇ／日又はそれ以下で経口投与される、項１３記載の方法。
［項２３］
アセチルコリンエステラーゼ阻害剤がドネペジルであり、且つ１．０ｍｇ／日又はそれ以下で経口投与される、項１３記載の方法。
［項２４］
アセチルコリンエステラーゼ阻害剤が、定常状態で１０〜６５％の赤血球アセチルコリンエステラーゼ阻害を達成する投与量で投与される、項１記載の方法。
［項２５］
（Ｒ）−７−クロロ−Ｎ−（キヌクリジン−３−イル）ベンゾ［ｂ］チオフェン−２−カルボキサミド又はその製薬上許容しうる塩、及びアセチルコリンエステラーゼ阻害剤を含有する医薬組成物。
［項２６］
アセチルコリンエステラーゼ阻害剤がタクリン、ドネペジル、リバスチグミン及びガランタミンから選択される、項２５記載の医薬組成物。
［項２７］
アセチルコリンエステラーゼ阻害剤がドネペジル、リバスチグミン及びガランタミンから選択される、項２５記載の医薬組成物。
［項２８］
アセチルコリンエステラーゼ阻害剤がドネペジル及びリバスチグミンから選択される、項２５記載の医薬組成物。
［項２９］
アセチルコリンエステラーゼ阻害剤がドネペジルである、項２５記載の医薬組成物。
［項３０］
１．０ｍｇ以下の（Ｒ）−７−クロロ−Ｎ−（キヌクリジン−３−イル）ベンゾ［ｂ］チオフェン−２−カルボキサミド又はその製薬上許容しうる塩、アセチルコリンエステラーゼ阻害剤及び製薬上許容しうる担体を含有する、１日単位投与量医薬組成物。
［項３１］
０．５ｍｇ以下の（Ｒ）−７−クロロ−Ｎ−（キヌクリジン−３−イル）ベンゾ［ｂ］チオフェン−２−カルボキサミド又はその製薬上許容しうる塩を含有する、項３０記載の１日単位投与量医薬組成物。
［項３２］
０．３ｍｇ以下の（Ｒ）−７−クロロ−Ｎ−（キヌクリジン−３−イル）ベンゾ［ｂ］チオフェン−２−カルボキサミド又はその製薬上許容しうる塩を含有する、項３１記載の１日単位投与量医薬組成物。
［項３３］
０．１ｍｇ以下の（Ｒ）−７−クロロ−Ｎ−（キヌクリジン−３−イル）ベンゾ［ｂ］チオフェン−２−カルボキサミド又はその製薬上許容しうる塩を含有する、項３１記載の１日単位投与量医薬組成物。
［項３４］
５ｍｇ以下のドネペジルを含有する、項３１記載の１日単位投与量医薬組成物。
［項３５］
４ｍｇ以下のドネペジルを含有する、項３１記載の１日単位投与量医薬組成物。
［項３６］
２．５ｍｇ以下のドネペジルを含有する、項３１記載の１日単位投与量医薬組成物。
［項３７］
１ｍｇ以下のドネペジルを含有する、項３１記載の１日単位投与量医薬組成物。
［項３８］
（Ｒ）−７−クロロ−Ｎ−（キヌクリジン−３−イル）ベンゾ［ｂ］チオフェン−２−カルボキサミド又はその製薬上許容しうる塩を含有する第１の単位投与量医薬組成物、及びアセチルコリンエステラーゼ阻害剤を含有する第２の単位投与量医薬組成物を含むパッケージを含む、包装された医薬品。
References
Boess, FG, Hendrix, M., van der Staay, FJ, Erb, C., Schreiber, R., van Staveren, W., de Vente, J., Prickaerts, J., Blokland, A., Koenig, G ., 2004. Inhibition of
Blokland, A., Prickaerts, J., Honig, W., De Vente, J., 1998. State-dependent impairment in object recognition after hippocampal NOS inhibition. NeuroReport 9, 4205-4208.
Ennaceur, A., Delacour, J., 1988. A new one-trial test for neurobiological studies of memory in rats.1: Behavioral data. Behav. Brain Res. 31, 47-59.
Ennaceur, A., Meliani, K., 1992. Effects of physostigmine and scopolamine on rats' performances in object-recognition and radial-maze tests.Psychopharmacology 109, 321-330.
Ennaceur, A., Cavoy, A., Costa, JC, Delacour, J. 1989. A new one-trial test for neurobiological studies of memory in rats. II: Effects of piracetam and pramiracetam. Behav. Brain Res. 33, 197 -207.
De Bruin, NMWJ, Prickaerts, J., Akkerman, S., Lange, JHM, Andriambeloson, E., De Haan, M., Wijnen, J., Van Drimmelen, M., Hissink, E., Heijnk, L. Kruse, CG (In Press) SLV330, a cannabinoid CB1 receptor antagonist, ameliorates deficits in the T-maze, object recognition and social recognition tasks in rodents. Neurobiol. Learn. Mem.
Prickaerts, J., Steinbusch, HWM, Smits, JFM, De Vente, J., 1997. Possible role of nitric oxide-cyclic GMP pathway in object recognition memory: Effects of 7-nitroindazole and zaprinast. Eur. J. Pharmacol. 337 , 125-136.
Prickaerts, J., Sik, A., van Staveren, WC, Koopmans, G., Steinbusch, HW, van der Staay, FJ, de Vente, J., Blokland, A., 2004. Phosphodiesterase type 5 inhibition improves early memory consolidation of object information. Neurochem Int. 45, 915-928.
Prickaerts, J., Sik, A., van der Staay, FJ, de Vente, J., Blokland, A., 2005. Dissociable effects of acetylcholinesterase inhibitors and phosphodiesterase type 5 inhibitors on object recognition memory: acquisition versus consolidation. Psychopharmacology 177 , 381-390.
According to the present invention, the following aspects are provided.
[Claim 1]
Cognition comprising administering to a patient (R) -7-chloro-N- (quinuclidin-3-yl) benzo [b] thiophene-2-carboxamide or a pharmaceutically acceptable salt thereof, and an acetylcholinesterase inhibitor How to improve functionality.
[Section 2]
[Section 3]
[Claim 4]
[Section 5]
A method according to any preceding paragraph, wherein the acetylcholinesterase inhibitor is selected from tacrine, donepezil, rivastigmine and galantamine.
[Claim 6]
Item 6. The method according to Item 5, wherein the acetylcholinesterase inhibitor is selected from donepezil, rivastigmine, and galantamine.
[Claim 7]
Item 6. The method according to Item 5, wherein the acetylcholinesterase inhibitor is selected from donepezil and rivastigmine.
[Section 8]
An acetylcholinesterase inhibitor for a period of time before the patient is administered (R) -7-chloro-N- (quinuclidin-3-yl) benzo [b] thiophene-2-carboxamide or a pharmaceutically acceptable salt thereof The method according to any one of the preceding clauses, wherein
[Claim 9]
Item 9. The method according to Item 8, wherein the previous administration is for at least one month.
[Section 10]
Item 10. The method according to Item 9, wherein the previous administration is for at least 3 months.
[Section 11]
Item 11. The method according to Item 10, wherein the previous administration is for at least 6 months.
[Claim 12]
The method of any of the preceding paragraphs that improves one or more of the following: learning, delayed memory, attention, working memory, visual learning, processing speed, vigilance, language learning, visual motor function, social cognition, long-term Memory or execution function.
[Claim 13]
Asymptomatic dosage of one or both of (R) -7-chloro-N- (quinuclidin-3-yl) benzo [b] thiophene-2-carboxamide or a pharmaceutically acceptable salt thereof and an
[Section 14]
[Section 15]
Item 13. The (R) -7-chloro-N- (quinuclidin-3-yl) benzo [b] thiophene-2-carboxamide or a pharmaceutically acceptable salt thereof is orally administered at less than 0.5 mg / day. the method of.
[Section 16]
[Section 17]
Item 13. The (R) -7-chloro-N- (quinuclidin-3-yl) benzo [b] thiophene-2-carboxamide or a pharmaceutically acceptable salt thereof is orally administered at a dose of less than 0.1 mg / day. the method of.
[Section 18]
[Section 19]
[Section 20]
[Claim 21]
[Item 22]
[Section 23]
[Claim 24]
[Claim 25]
A pharmaceutical composition containing (R) -7-chloro-N- (quinuclidin-3-yl) benzo [b] thiophene-2-carboxamide or a pharmaceutically acceptable salt thereof, and an acetylcholinesterase inhibitor.
[Claim 26]
Item 26. The pharmaceutical composition according to Item 25, wherein the acetylcholinesterase inhibitor is selected from tacrine, donepezil, rivastigmine and galantamine.
[Section 27]
Item 26. The pharmaceutical composition according to Item 25, wherein the acetylcholinesterase inhibitor is selected from donepezil, rivastigmine, and galantamine.
[Claim 28]
Item 26. The pharmaceutical composition according to Item 25, wherein the acetylcholinesterase inhibitor is selected from donepezil and rivastigmine.
[Item 29]
Item 26. The pharmaceutical composition according to Item 25, wherein the acetylcholinesterase inhibitor is donepezil.
[Section 30]
1.0 mg or less of (R) -7-chloro-N- (quinuclidin-3-yl) benzo [b] thiophene-2-carboxamide or a pharmaceutically acceptable salt thereof, an acetylcholinesterase inhibitor and a pharmaceutically acceptable A daily unit dosage pharmaceutical composition comprising a carrier.
[Claim 31]
31. A daily unit according to Item 30, containing 0.5 mg or less of (R) -7-chloro-N- (quinuclidin-3-yl) benzo [b] thiophene-2-carboxamide or a pharmaceutically acceptable salt thereof. Dosage pharmaceutical composition.
[Section 32]
Item 32. The daily unit according to Item 31, comprising 0.3 mg or less of (R) -7-chloro-N- (quinuclidin-3-yl) benzo [b] thiophene-2-carboxamide or a pharmaceutically acceptable salt thereof. Dosage pharmaceutical composition.
[Section 33]
Item 31. The daily unit according to Item 31, containing 0.1 mg or less of (R) -7-chloro-N- (quinuclidin-3-yl) benzo [b] thiophene-2-carboxamide or a pharmaceutically acceptable salt thereof. Dosage pharmaceutical composition.
[Section 34]
Item 32. A daily unit dose pharmaceutical composition according to Item 31, comprising 5 mg or less of donepezil.
[Claim 35]
Item 32. A daily unit dose pharmaceutical composition according to Item 31, comprising 4 mg or less of donepezil.
[Claim 36]
Item 32. A daily unit dose pharmaceutical composition according to Item 31, comprising 2.5 mg or less of donepezil.
[Section 37]
Item 32. A daily unit dose pharmaceutical composition according to Item 31, comprising 1 mg or less of donepezil.
[Section 38]
(R) -7-chloro-N- (quinuclidin-3-yl) benzo [b] thiophene-2-carboxamide or a first unit dose pharmaceutical composition containing a pharmaceutically acceptable salt thereof, and acetylcholinesterase A packaged medicament comprising a package comprising a second unit dose pharmaceutical composition containing an inhibitor.
Claims (20)
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| EP2429518A1 (en) | 2012-03-21 |
| ECSP11011453A (en) | 2011-12-30 |
| CL2011002847A1 (en) | 2012-07-20 |
| PE20120324A1 (en) | 2012-04-17 |
| CA2761716A1 (en) | 2010-11-18 |
| CN102802620A (en) | 2012-11-28 |
| RU2011150248A (en) | 2013-06-20 |
| BRPI1014793A2 (en) | 2016-04-05 |
| CO6460746A2 (en) | 2012-06-15 |
| WO2010132423A1 (en) | 2010-11-18 |
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